Major depression during pregnancy and the postpartum period is a major women's health concern. Previous investigations have demonstrated that maternal depression during pregnancy is a risk factor for pre-term birth and low birth weight, negative effects on child development and altered neuroendocrine responses and neurotransmitter levels in children. A recently completed collaborative investigation of predictors of maternal depression during pregnancy, demonstrated a 68% relapse rate for those discontinuing antidepressants and remarkably a 28% relapse rate in women who choose to continue antidepressants. Despite the clear public- health importance of depression during pregnancy, and the likelihood that some women may be genetically vulnerable to develop depression independent of treatment choices, the research assessing genetic factors influencing vulnerability for depression during pregnancy are sparse. This proposal will begin to address this understudied area of women's health research consistent with themes in two program announcements: Women's Mental Health in Pregnancy and Postpartum (PA-03-135) and Women's Mental Health and Sex/Gender Differences in Research (PA-03-143). The current proposal will examine the genetic influences on neurohormonal alterations that are potential modulators of maternal risk for depression during pregnancy and is planned as an Exploratory/Developmental grant (R21) in response to PA-03-135. The overarching hypothesis guiding the current proposal is that glucocorticoids and progesterone alter the expression of the glucocorticoid receptor (GR)-regulating co-chaperone FKBP5 and other GR-associated regulatory molecules, during pregnancy, leading to adaptive GR resistance during this period. Dysfunction of GR regulation due to sequence variation in genes encoding such regulatory proteins may leave some women vulnerable to GR-mediated deleterious effects in key brain regions, thus predisposing them to depressive symptoms during the ante- and postpartum periods. Relevance to public health: Expanding the knowledge base on the genetic mechanisms potentially contributing to maternal depression during pregnancy will facilitate early identification of women at risk. Such 'a priori' identification of women at risk will directly contribute to treatment planning and enhancement of perinatal health, obstetrical outcome, and infant well-being. [unreadable] [unreadable] [unreadable]